Summary This study examines the effects of diet on peripheral metabolism and central nervous system (CNS) phenotypes and pathways implicated in early-stage Alzheimer's disease (AD) pathology in nonhuman primates (NHPs). The premise for the study is based on evidence that dietary patterns are powerful modulators of brain aging. Habitual consumption of simple sugars and saturated fat, characteristic of a Western diet, is associated with chronic diseases and increased risk of AD and vascular cognitive impairment. Conversely, high intake of dietary fruits and vegetables, fish, and healthy fats, characteristic of a Mediterranean diet, is associated with reduced risk of chronic diseases, AD, and vascular cognitive impairment. Evidence supporting these associations comes from population-based studies that may be affected by confounders, or from rodent studies with limited translational relevance. Identification of specific mechanisms underlying dietary effects has been challenging to date. However, in our 1-month randomized trial in older adults comparing Western and prudent diet, we observed changes in AD and pathologic aging markers (e.g. cerebrospinal fluid A?42, lipoproteins, insulin, and oxidative stress markers), suggesting that Western diet composition may alter the brain in ways that promote AD-related neuropathologies. Nonhuman primates offer unique opportunities to model complex human diseases, and we and others have shown that they develop AD pathology and diet- related metabolic and vascular disorders with aging. The proposed study leverages a NIH-funded investigation in which adult female cynomolgus monkeys were randomized to consume a Western or Mediterranean-like diet for 30 months. Metabolic, vascular, and behavioral phenotyping, MR imaging, and serial collections of cerebrospinal fluid occurred in the Baseline and Treatment phases. At necropsy, multiple peripheral and vascular tissues were obtained and the brains collected using a protocol adapted from human AD guidelines. We now propose to use these archived tissue, images, and data to determine the effects of Western vs. Mediterranean diet on structural and functional CNS characteristics relevant to AD risk. Our overarching hypothesis is that, compared to a Western diet, consuming a Mediterranean diet protects against neuropathologic, vascular, inflammatory, oxidative, and other phenotypes associated with increased risk of AD. Our Specific Aims are to determine effects of Western and Mediterranean diets on: AD neuropathology, neurovascular pathophysiology, neuroinflammation, oxidative stress, and gene expression to identify the peripheral mediators of diet effects on the CNS, and novel pathways and mechanisms which may be involved in diet/AD interactions.